This application is a 371 of PCT/EP00/00192 filed Jan. 13, 2000.
The invention relates to novel N-oxides, which are used in the pharmaceutical industry for the production of medicaments.
Chem.Ber. 1939, 72, 675-677, J. Chem. Soc., 1956, 4280-4283 and J. Chem. Soc.(C), 1971, 1805 describe the synthesis of 6-phenylphenanthridines. The International Applications WO 97128131 and WO 97/35854 describe 6-phenyl- and 6-pyridylphenanthridines as PDE4 inhibitors.
It has now been found that the novel N-oxides of substituted 6-phenylphenanthridines described in greater detail below have surprising and particularly advantageous properties.
The invention thus relates to the N-oxides of the compounds of the formula I, 
in which
R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is hydrogen or 1-4C-alkyl,
R31 is hydrogen or 1-4C-alkyl,
or in which
R3 and R31 together are a 1-4C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together represent an additional bond,
R6 is an R7-substituted phenyl radical, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
Ar is an unsubstituted or R9- and/or R10-substituted phenyl radical, and
R9 and R10 independently of one another are halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl or 1 -4C-alkoxy.
1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
As completely or predominantly fluorine-substituted 1-4C-alkoxy, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals may be mentioned. xe2x80x9cPredominantlyxe2x80x9d in this connection means that more than half of the hydrogen atoms are replaced by fluorine atoms.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy [xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94] and the ethylenedioxy [xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94] radicals.
If R3 and R31 together have the meaning 1-4C-alkylene, the positions 1 and 4 in the N-oxides of the compounds of the formula I are linked to one another by a 1-4C-alkylene bridge, 1-4C-alkylene representing straight-chain or branched alkylene radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the radicals methylene [xe2x80x94CH2xe2x80x94], ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2], 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94] and isopropylidene [xe2x80x94C(CH3)2xe2x80x94].
If R5 and R51 together are an additional bond, then the carbon atoms in positions 2 and 3 in the N-oxides of the compounds of the formula I are linked to one another via a double bond.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Preferably, the 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may be mentioned.
Ar-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the aryl radicals defined above. Examples which may be mentioned are the p-methoxybenzyl, the phenethyl and the benzyl radicals.
Halogen within the meaning of the invention is bromine, chlorine or fluorine.
It is known to the person skilled in the art that the N-oxides according to the invention, when they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also includes all solvates and in particular all hydrates of the N-oxides according to the invention.
The N-oxides of the compounds of the formula I to be emphasized are those in which
R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 3-SC-cycloalkoxy, 3-5C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is hydrogen or 1-2C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together represent an additional bond,
R6 is an R7-substituted phenyl radical, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
Ar is an unsubstituted or R9- and/or R10-substituted phenyl radical, and
R9 and R10 independently of one another are 1-4C-alkyl or 1-4C-alkoxy.
The N-oxides of the compounds of the formula I particularly to be emphasized are those in which
R1 is 1-2C-alkoxy,
R2 is 1-2C-alkoxy,
R3, R31, R4, R5 and R51 are hydrogen,
R6 is an R7-substituted phenyl radical, where
R7 is a tetrazol-5yl radical substituted by a radical R8, where
R8 is 1-4C-alkyl, 5-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1 -2C-alkyl, where
Ar is an unsubstituted or R9-substituted phenyl radical, and
R9 is 1-2C-alkyl or 1-2C-alkoxy.
Preferred N-oxides of the compounds of the formula I are those in which
R1 is 1-2C-alkoxy,
R2 is 1-2C-alkoxy,
R3, R31, R4, R5 and R51 are hydrogen,
R6 is an R7-substituted phenyl radical, where
R7 is an R8-substituted 2H-tetrazol-5-yl radical, and
R8 is 1-2C-alkyl.
The N-oxides of the compounds of the formula I are chiral compounds having chiral centers in positions 4a and 10b and, depending on the meaning of the substituents R3, R31, R4, R5 and R51, further chiral centers in the positions 1, 2, 3 and 4.
The invention therefore comprises all conceivable pure diastereomers and pure enantiomers and their mixtures in any mixing ratio, including the racemates. The N-oxides of the compounds of the formula I are preferred in which the hydrogen atoms in positions 4a and 10b are cis to one another. The pure cis enantiomers are particularly preferred.
In this connection, particularly preferred N-oxides of the compounds of the formula I are those in which positions 4a and 10b have the same absolute configuration as the compound (-)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene employable as a starting compound and having the optical rotation [xcex1]D20=xe2x88x9258.5xc2x0 (c=1, ethanol).
The enantiomers can be separated in a manner known per se (for example by preparation and separation of appropriate diastereoisomeric compounds).
Preferably, an enantiomer separation is carried out at the stage of the starting compounds of the formula III 
for example by means of salt formation of the racemic compounds of the formula III with optically active carboxylic acids. Examples which may be mentioned in this connection are the enantiomeric forms of mandelic acid, tartaric acid, O,Oxe2x80x2-dibenzoyltartaric acid, camphoric acid, quinic acid, glutamic acid, malic acid, camphorsulfonic acid, 3-bromocamphorsulfonic acid, xcex1-methoxyphenylacetic acid, xcex1-methoxy-xcex1-trifluoromethylphenylacetic acid and 2-phenylpropionic acid. Alternatively, enantiomerically pure starting compounds of the formula III can also be prepared via asymmetric syntheses.
The tetrazol-5-yl radical R7 of the N-oxides of the compounds of the formula I can be bonded to the phenyl radical R6 either in the ortho, meta or para position to the phenanthridine ring.
Preferred N-oxides according to the invention are those in which the tetrazol-5-yl radical R7 is bonded to the phenyl radical R6 in the meta or para position to the phenanthridine ring. In this connection, the N-oxides according to the invention are particularly preferred in which the tetrazol-5-yl radical R7 is bonded in the para position.
The N-oxides of the compounds of the formula I can be prepared for example, by the process described below in greater detail.
The process comprises subjecting compounds of the formula I in which R1, R2, R3, R31, R4, R5, R51 and R6 have the meanings indicated above, to an N-oxidation.
The N-oxidation is carried out in a manner familiar to the person skilled in the art, e.g. with the aid of hydrogen peroxide in methanol or with the aid of N-chloroperoxybenzoic acid in dichloromethane at room temperature. The person skilled in the art will be familiar on the basis of his/her expert knowledge with the reaction conditions which are specifically necessary for carrying out the N-oxidation.
Compounds of the formula 1, in which R1, R2, R3, R31, R4, R5, R51, R6, R7 and R8 (R8xe2x89xa0H) have the meanings indicated above, can be prepared from the corresponding compounds of the formula II by a cyclocondensation reaction. 
Compounds of the formula I in which R1, R2, R3, R31, R4, R5, R51, R6 and R7 have the meanings indicated above and R8 is hydrogen can be obtained from the corresponding compounds of the formula I in which R6 is cyanophenyl by reaction with alkali metal azides and halogen salts of ammonia. The 1H- and 2H-tetrazol-5-yl radicals of these compounds can then be subjected, optionally, to an alkylation reaction.
The alkylation reaction is expediently carried out analogously to the methods known to the person skilled in the art, e.g. by reaction of the 1H- or 2H-tetrazole compounds of the formula I with compounds of the formula R8-X in the presence of a base, where R8 has the abovementioned meaningsxe2x80x94excluding hydrogenxe2x80x94and X is a suitable leaving group such as, for example, a chlorine, bromine or iodine atom or an alkylsulfate radical. The 1- and 2-substituted tetrazole regioisomer mixtures usually formed in the alkylation are separated by methods known to the person skilled in the art, such as crystallization or chromatography on suitable support materials. An analogous alkylation of tetrazoles and separation of the regioisomers is described, for example, in J. Med. Chem. 1996, 39, 2354.
The reaction of cyanophenyl derivatives with alkali metal azides and halogen salts of ammonia to give 2-, 3- or 4-(1H- or 2H-tetrazol-5-yl)phenyl derivatives which are unsubstituted in the tetrazole moiety is described, for example, in J. Med. Chem. 1993, 36, 3246.
The cyclocondensation is carried out in a manner known per se to the person skilled in the art, according to Bischler-Napieralski (e.g. as described in J. Chem. Soc., 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or preferably phosphorus oxychloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without further solvent using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.
Compounds of the formula II in which R1, R2, R3, R31, R4, R5, R51 and R6 have the meanings indicated above are accessible from the corresponding compounds of the formula III, in which R1, R2, R3, R31, R4, R5 and R51 have the meanings indicated above, by reaction with compounds of the formula R6-COxe2x80x94X, in which R6 has the meaning indicated above and X represents a suitable leaving group, preferably a chlorine atom. For example, the benzoylation is carried out as described in the following examples according to the Einhorn process, the Schotten-Baumann variant or as in J. Chem. Soc. (C), 1971, 1805-1808.
Compounds of the formula R6-COxe2x80x94X and compounds of the formula III are either known or can be prepared in a known manner.
Compounds of the formula R6-COxe2x80x94X can be prepared, for example, from the corresponding carboxylic acids R6-COOH, in which R6 has the meaning indicated above, by reaction in a manner familiar to the person skilled in the art.
The compounds R6-COOH in which R6 has the meaning indicated above are either known or can be obtained from alkyl 2-, 3- or 4-cyanobenzoates in a manner known to the person skilled in the art, e.g. by reaction with alkali metal azides and halogen salts of ammonia to give alkyl 2-, 3- or 4-(1H- or 2H-tetrazol-5-yl)benzoates which are unsubstituted in the tetrazole moiety. Such a reaction is described, for example, in J. Med. Chem. 1993, 36, 3246. Optionally, these intermediate compounds can be convertedxe2x80x94as described above for the 1H- or 2H-tetrazole compounds of the formula I or in the abovementioned literaturexe2x80x94by alkylation with compounds of the formula R8-X in the presence of a base into alkyl R6-carboxylates in which R6 is an R7-substituted phenyl radical, R7 is an R8-substituted 1H- or 2H-tetrazol-5-yl radical and R8 is not hydrogen, but has one of the other meanings mentioned above for R8. The alkyl R6-carboxylates are converted into the free carboxylic acids R6-COOH by means of alkaline or acidic hydrolysis conditions familiar to the person skilled in the art.
The compounds of the formula III can be prepared, for example, from compounds of the formula IV, 
in which R1, R2, R3, R31, R4, R5 and R51 have the abovementioned meanings, by reduction of the nitro group.
The reduction is carried out in a manner known to the person skilled in the art, for example as described in J. Org. Chem. 1962, 27, 4426 or as described in the following examples.
The reduction can be carried out, for example, by catalytic hydrogenation, e.g. in the presence of Raney nickel, in a lower alcohol such as methanol or ethanol at room temperature and under normal or elevated pressure. Optionally, a catalytic amount of an acid, such as, for example, hydrochloric acid, can be added to the solvent. Preferably, however, the reduction is carried out using metals such as zinc or iron with organic acids such as acetic acid or mineral acids such as hydrochloric acid.
The compounds of the formula III in which R1, R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 together represent an additional bond can be prepared from the corresponding compounds of the formula IV by selective reduction of the nitro group in a manner known to the person skilled in the art, for example in the presence of Raney nickel in a lower alcohol as solvent using hydrazine hydrate as a hydrogen donor.
The compounds of the formula IV, in which R1, R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 are hydrogen, are either known or can be prepared from corresponding compounds of the formula IV in which R5 and R51 together are an additional bond. The reaction can be carried out in a manner known to the person skilled in the art, preferably by hydrogenation in the presence of a catalyst, such as, for example, palladium on active carbon, e.g. as described in J. Chem. Soc. (C), 1971, 1805-1808.
The compounds of the formula IV, in which R5 and R51 together are an additional bond, are either known or can be obtained by the reaction of compounds of the formula (V), 
in which R1 and R2 have the meanings mentioned above, with compounds of the formula VI,
R3xe2x80x94CHxe2x95x90C(R4)xe2x80x94C(R4)xe2x95x90CHxe2x80x94R31xe2x80x83xe2x80x83(VI)
in which R3, R31 and R4 have the meanings mentioned above.
Compounds of the formula IV, in which R5 and R51 together represent an additional bond and R3 and R31 together are a 1-4C-alkylene group can, for example, be obtained by reaction of cyclic compounds of the formula VI, in which R4 has the above-mentioned meanings and R3 and R31 together are a 1-4C-alkylene group [for example cyclohexa-1,3-dien, 2,3-dimethylcyclohexa-1,3-dien, cyclohepta-1,3-dien, 2,3-dimethylcyclohepta-1,3-dien or cycloocta-1,3-dien] with compounds of the formula V, in which R1 and R2 have the above-mentioned meanings.
The cycloaddition is in this case carried out in a manner known to the person skilled in the art according to Diels-Alder, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or in J. Org. Chem. 1952, 17, 581 or as described in the following examples.
Compounds of the formula IV obtained in the cycloaddition, in which the phenyl ring and the nitro group are trans to one another, can be converted in a manner known to the person skilled in the art into the corresponding cis compounds, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or as described in the following examples.
The compounds of the formulae V and VI are either known or can be prepared in a known manner. The compounds of the formula V can be prepared, for example, in a manner known to the person skilled in the art from corresponding compounds of the formula VII as described in, for example, J. Chem. Soc. 1951, 2524 or in J. Org. Chem. 1944, 9, 170 or as described in the following examples.
The compounds of the formula VII, 
in which R1 and R2 have the meanings indicated above, are either known or can be prepared in a manner known to the person skilled in the art, as described, for example, in Ber. Dtsch. Chem. Ges. 1925, 58, 203.
It is moreover known to the person skilled in the art that if there are a number of reactive centers on a starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
The isolation and purification of the substances according to the invention is carried out in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
The following examples serve to illustrate the invention further without restricting it. Likewise, further compounds of the formula 1, whose preparation is not explicitly described, can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques.